Process for the production of fluoromethylhexafluoroisopropylether

ABSTRACT

PCT No. PCT/GB96/03001 Sec. 371 Date Jun. 30, 1998 Sec. 102(e) Date Jun. 30, 1998 PCT Filed Dec. 6, 1996 PCT Pub. No. WO97/25303 PCT Pub. Date Jul. 17, 1997Process for producing Sevoflurane anaesthetic which comprises reacting hexafluoroisopropyl alcohol with essentially pure bis(fluoromethyl)ether. The bis(fluoromethyl)ether is preferably obtained by the reaction of formaldehyde with hydrogen fluoride.

This invention relates to a process for the production offluoromethylhexafluoroisopropylether of formula CH₂ F.CH(CF₃)₂ which isthe anaesthetic "Sevoflurane".

Several processes have been proposed for the production of Sevofluraneincluding the reaction of hexafluoroisopropyl alcohol, (CF₃)₂ CHOH, withformaldehyde and hydrogen fluoride. One such process comprising addinghexafluoroisopropyl alcohol to a mixture of paraformaldehyde andhydrogen fluoride plus sufficient sulphuric acid to sequester most ofthe water formed at a temperature above 57° C. is described in U.S. Pat.No. 4,250,334. A similar process comprising mixing hexafluoroisopropylalcohol, formaldehyde, hydrogen fluoride and a dehydrating agent such assulphuric acid is described in U.S. Pat. No. 4,469,898.

A process for producing an alpha-fluoroether such as and includingSevoflurane is described in International Patent Publication No WO93/12057, the process comprising reacting a non-enolisable aldehyde suchas formaldehyde with hydrogen fluoride to form an intermediate andreacting the intermediate with an alcohol such as hexafluoroisopropylalcohol to form an alpha-fluoroether such as Sevofluorane. Theproduction of Sevoflurane by adding hexafluoroisopropyl alcohol to thereaction mixture derived from trioxane (as the source of formaldehyde)and hydrogen fluoride and containing the intermediatebis(fluoromethyl)ether is described in Example 19.

As is described in WO 93/12057, the reaction products obtained inExample 19 comprised mainly unreacted hexafluoroisopropyl alcohol (72%by mass spectroscopic analysis) and unreacted bis(fluoromethyl)ether(22%) and the yield of Sevoflurane was only 4.9%. This very low yield ofSevoflurane renders the process unsuitable or at best barely suitablefor industrial application even with recovery anti recycle of unreactedhexafluoroisopropyl alcohol and bis(fluoromethyl)ether.

The present invention is based on the discovery that separation of theintermediate bis(fluoromethyl)ether from the reaction mixture beforeaddition of the hexafluoroisopropyl alcohol results in a process inwhich Sevoflurane is obtained in high yield and in particular can beobtained as the major product of the reaction.

According to the present invention there is provided a process for theproduction of fluoromethylhexafluoroisopropylether [Sevoflurane] whichcomprises reacting essentially pure bis(fluoromethyl) ether withhexafluoroisopropyl alcohol and recovering the resultingfluoromethylhexafluoroisopropylether from the reaction products.

The bis(fluoromethyl)ether is conveniently and preferably produced bythe reaction of formaldehyde or a source of formaldehyde with hydrogenfluoride and according to a particular embodiment of the invention thereis provided a process for the production offluoromethylhexafluoroisopropylether which comprises reactingformaldehyde with hydrogen fluoride to produce a reaction mixturecontaining bis(fluoromethyl)ether, separating essentially purebis(fluoromethyl)ether from the reaction mixture, reacting the resultingessentially pure bis(fluoromethyl)ether with hexafluoroisopropyl alcoholand recovering the resulting fluoromethylhexafluoroisopropylether fromthe reaction products.

The reaction between the bis(fluoromethyl)ether and thehexafluoroisopropyl alcohol is conveniently carried out at ambienttemperature, say 20° C. to 30° C. and at atmospheric pressure, althoughif desired subatmospheric or superatmospheric pressure and a range oftemperatures from about 0° C. to about 100° C. may be employed. Thereaction is preferably carried out in the presence of an acid such assulphuric acid. A slight exotherm resulting in a rise in temperature ofthe reaction mixture may be observed but in general there is no realadvantage in applying heat to the reaction mixture.

The reaction can be readily carried out to result in complete conversionof the hexafluoroisopropyl alcohol and with an acceptable selectivity tothe desired Sevoflurane product although a significant amount, say 20%or more, of the acetal (CF₃)₂ CHOCH₂ OCH₂ F is usually produced as aby-product. It is a matter of mere routine experimentation to optimisethe reaction conditions to maximise the yield of Sevoflurane andminimise the yield of by-products such as the metal. A reaction productmixture in which Sevoflurane is the major component with a yield of atleast about 55% and preferably about 60% or more is obtained. Carryingout the reaction with complete conversion of the hexafluoroisopropylalcohol obviates the need to recover and recycle unreacted alcohol.

The amounts of bis(fluoromethyl)ether and hexafluoroisopropyl alcoholwill usually be such that the molar ratio of the ether to the alcohol isfrom about 0.5:1 to about 1.5:1. In general about equimolar amounts ofether and alcohol or an excess of the ether will be used to ensurecomplete conversion of the alcohol. However, it has been observed that alarge excess of the ether is undesirable in that it tends to result inthe formation of a precipitate of granular crystals (possibly due topolymerisation of products of decomposition of the ether) and we preferto employ a mole ratio of ether to alcohol of no greater than about 2:1.

The separation, recovery and purification of Sevoflurane from productstreams containing it is known and any of the known methods may be usedin the process of the invention. Such methods will usually include atleast one distillation step and will usually include a step ofseparating and recovering any bis(fluoromethyl)ether present in theproduct stream. The ether recovered from the product stream can berecycled to the reaction with hexafluoroisopropyl alcohol.

The process can be operated as a batch or continuous process or acombination thereof but is preferably operated as a continuous processwith recycle of recovered bis(fluoromethyl)ether.

As stated herinbefore, a prefered embodiment of the invention includesthe step of producing the bis(fluoromethyl)ether by reaction offormaldehyde (or a polymeric form of formaldehyde such asparaformaldehyde or trioxane) with hydrogen fluoride. Any of the knownmethods for production of the bis(fluoromethyl)ether may be employed asthe ether formation step of this embodiment of the present invention.The production of bis(fluoromethyl)ether from formaldehyde and hydrogenfluoride is described, for example, in European Patent Publication No.518,506 and in International Patent Publications No. WO 93/10070, WO93/12057 and WO 93/22265, the disclosures of which are incorporatedherein by reference. In the present invention we especially prefer toemploy the ether production process described in International PatentPublication No. WO 93/10070 which comprises reacting formaldehyde withhydrogen fluoride in a reaction-distillation column from which the etheris withdrawn in essentially pure form and in particular essentially freefrom water.

The invention is illustrated but in no way limited by the followingExample.

EXAMPLE.

Bis(fluoromethyl)ether (2 g) of purity approximately 99% was mixed withstirring into hexafluoroisopropyl alcohol (4.1 g) at room temperature(approximately 25° C.) and pressure and sulphuric acid (1 ml of 98%acid) was added to the mixture. A slight exotherm was noted. After 10minutes, the mixture was neutralised by adding sodium hydroxide and thenanalysed by gas chromatography/mass spectometry.

The composition of the product mixture determined by GC/MS analysis was:

    ______________________________________                                                      % age of mixture                                                ______________________________________                                        Sevoflurane     59.7                                                          Acetal*                            21.6                                       Bis(fluoromethyl)ether                                                                            17.1                                                      Methyl formate               1.6                                                                                        100                                 ______________________________________                                    

For purposes of comparison the product mixture obtained in Example 19 ofWO 93/12057 was determined by GC/MS analysis to be:

    ______________________________________                                                      % age of mixture                                                ______________________________________                                        Sevoflurane     4.9                                                           Acetal*                             1.3                                       Bis(fluoromethyl)ether                                                                            22.2                                                      Hexafluoroisopropanol                                                                              71.6                                                     ______________________________________                                    

We claim:
 1. A process for the production offluoromethylhexafluoroisopropylether which comprises reactingessentially pure bis(fluoromethyl)ether with hexafluoroisopropyl alcoholand recovering the resulting fluoromethylhexafluoroisopropylether fromthe reaction products.
 2. A process as claimed in claim 1 whichcomprises reacting formaldehyde with hydrogen fluoride to produce areaction mixture containing bis(fluoromethyl)ether, separatingessentially pure bis(fluoromethyl)ether from the reaction mixture andreacting the essentially pure bis(fluoromethyl)ether withhexafluoroisopropyl alcohol.
 3. A process as claimed in claims 1 inwhich the essentially pure bis(fluoromethyl)ether is reacted withhexafluoroisopropyl alcohol in the presence of an acid.
 4. A process asclaimed in claim 1 in which the molar ratio of bis(fluoromethyl)ether tohexafluoroisopropyl alcohol is 0.5:1 to 2:1.
 5. A process as claimed inclaim 1 in which the yield offluoromethyl(hexafluoromethylhexafluoroisopropylether is at least about55%.